The aim of this study is to determine the impact of pathogenic tau accumulation on synaptic structure and function in a new mouse model of human tau pathology (hTau mice). Using a newly developed membrane labeling technique to visualize hippocampal and cortical synapses in fixed brain slices, we will determine changes in spine density, length and diameter of dendrites, and the number of presynaptic terminals at different stages of tau pathology. We will also reveal whether the initial effects of abnormal tau accumulation are on pre- or postsynaptic structures, and whether such effects are cell-type and region specific, In order to better understand the time scale of synaptic changes associated with tau pathology, we will use a transcranial two-photon imaging technique to follow the same fluorescently-labeled synapses over extended periods of time (days to months) in living hTau mice. In combination with in vivo imaging approaches, serial electron microscopy will be used to further explore ultrastructural correlates of synaptic abnormalities. To investigate synaptic dysfunction in hTau mice, we will determine if calcium dynamics are altered in dendritic shafts and spines in acute brain slices, and if the disruption of dendritic functionality occurs prior to any structural alterations. Together, these studies will provide us a wealth of information on synaptic dysfunction in the mouse model of tau pathology at an unprecedented high spatial and temporal resolution. Because synapse dysfunction and pathogenic tau accumulation are two prominent features in Alzheimer's disease (AD), determining the relationship between these two components and cellular mechanisms underlying synapse loss is likely to be important for understanding the pathogenesis of AD and for developing new therapeutic approaches.